Endoscopic therapy is increasingly being used in the treatment of high-grade intraepithelial neoplasia (HGIN) and mucosal adenocarcinoma (BC) in patients with Barrett’s oesophagus. This report provides 5 year follow-up data from a large prospective study investigating the efficacy and safety of endoscopic treatment in these patients and analysing risk factors for recurrence.
Prospective case series.
Academic tertiary care centre.
Between October 1996 and September 2002, 61 patients with HGIN and 288 with BC were included (173 with short-segment and 176 with long-segment Barrett’s oesophagus) from a total of 486 patients presenting with Barrett’s neoplasia. Patients with submucosal or more advanced cancer were excluded.
Endoscopic therapy.
Rate of complete remission and recurrence rate, tumour-associated death.
Endoscopic resection was performed in 279 patients, photodynamic therapy in 55, and both procedures in 13; two patients received argon plasma coagulation. The mean follow-up period was 63.6 (SD 23.1) months. Complete response (CR) was achieved in 337 patients (96.6%); surgery was necessary in 13 (3.7%) after endoscopic therapy failed. Metachronous lesions developed during the follow-up in 74 patients (21.5%); 56 died of concomitant disease, but none died of BC. The calculated 5 year survival rate was 84%. The risk factors most frequently associated with recurrence were piecemeal resection, long-segment Barrett’s oesophagus, no ablative therapy of Barrett’s oesophagus after CR, time until CR achieved >10 months and multifocal neoplasia.
This study showed that endoscopic therapy was highly effective and safe, with an excellent long-term survival rate. The risk factors identified may help stratify patients who are at risk for recurrence and those requiring more intensified follow-up.
With the introduction of laparoscopic antireflux surgery (LARS) for gastro-oesophageal reflux disease (GORD) along with the increasing efficacy of modern medical treatment, a direct comparison is warranted. The 3-year interim results of a randomised study comparing both the efficacy and safety of LARS and esomeprazole (ESO) are reported.
LOTUS is an open, parallel-group multicentre, randomised and controlled trial conducted in dedicated centres in 11 European countries. LARS was completed according to a standardised protocol, comprising a total fundoplication and a crural repair. Medical treatment comprised ESO 20 mg once daily, which could be increased stepwise to 40 mg once daily and then 20 mg twice daily in the case of incomplete GORD control. The primary outcome variable was time to treatment failure (Kaplan–Meier analysis). Treatment failure was defined on the basis of symptomatic relapse requiring treatment beyond that stated in the protocol.
554 patients were randomised, of whom 288 were allocated to LARS and 266 to ESO. The two study arms were well matched. The proportions of patients who remained in remission after 3 years were similar for the two therapies: 90% of surgical patients compared with 93% medically treated for the intention to treat population, p = 0.25 (90% vs 95% per protocol). No major unexpected postoperative complications were experienced and ESO was well tolerated. However, postfundoplication complaints remain a problem after LARS.
Over the first 3 years of this long-term study, both laparoscopic total fundoplication and continuous ESO treatment were similarly effective and well-tolerated therapeutic strategies for providing effective control of GORD.
To compare a Helicobacter pylori "test and treat" strategy with prompt endoscopy in young Asians with dyspepsia.
A randomised, prospective study was carried out on uninvestigated dyspeptics aged <45 years in a single (academic) primary care centre. Patients were randomised to either a [13C]urea breath test (UBT) or prompt endoscopy (oesophagogastroduodenoscopy (OGD) and followed-up for 12 months.
432 patients (mean (SD) age 30 (8) years, male 46%, ethnicity: Malays 33.3%, Chinese 30.6%, Indians 34.7%) were randomised to UBT (n = 222) or OGD (n = 210). 387 (89.6%) patients completed the study. At 12 months, there was no difference in symptom change (measured by the Leeds Dyspepsia Questionnaire) between the two groups, but more patients were very satisfied (40.0% vs 21.6%, p<0.0001) in the OGD group. More additional endoscopy was performed in the UBT group (25 vs 10, p = 0.03), but medication consumption was higher in the OGD group (proton pump inhibitor 3.6 (8.8) vs 2.0 (7.5) weeks, p<0.001; H2 receptor antagonist 5.3 (9.7) vs 3.9 (9.2) weeks, p = 0.017; prokinetics 1.4 (4.7) vs 0.4 (2.5) weeks, p<0.001) and no differences in medical consultation were noted. The median cost of the initial prompt endoscopy approach at 12 months was significantly higher than a "test and treat" strategy (US$179.05 vs US$87.10, p<0.0001).
A H pylori "test and treat" strategy is more cost-effective but less satisfying than prompt endoscopy in the management of young Asian patients with uncomplicated dyspepsia.
The role of protease-activated receptor-2 (PAR2) during intestinal inflammation is still unclear due to the fact that PAR2-activating peptide has both pro- and anti-inflammatory properties. The aim of this study was to investigate the effects of PAR2 deficiency (using PAR2-deficient mice, PAR2–/–) in models of colitis, in order to elucidate the role of endogenous PAR2 in the process of inflammation in the gut.
Colonic inflammation in wild-type and PAR2–/– mice was induced by dextran sodium sulfate, trinitrobenzene sulfonic acid (TNBS), a T helper-1 predominant model, or oxazolone, a T helper-2 predominant model. Leukocyte recruitment, assessed by intravital microscopy, and inflammatory parameters (myeloperoxidase (MPO), macroscopic and microscopic damage) were assessed during the development of colitis. Lastly, the protein levels of cyclooxygenases (COXs) and adhesion molecules (ICAM-1, VCAM-1, alpha-M, alpha-4) were assessed by using western blot analysis.
In all three models of colitis, MPO activity, macroscopic damage score and bowel thickness were significantly lower in PAR2–/– mice. Changes in vessel leukocyte recruitment parameters (rolling and adhesion) were also significantly reduced in PAR2–/– mice compared to wild-type mice after the induction of colitis. The protein expression of ICAM-1, VCAM-1 and alpha-4 was significantly attenuated, whereas the expression of COX-1 was significantly increased in PAR2–/– mice challenged with TNBS-induced colitis.
The role of endogenous PAR2 in the gut is pro-inflammatory and independent of the T helper-1 or -2 cytokine profile. Endogenous PAR2 activation controls leukocyte recruitment in the colon and thus appears as a new potential therapeutic target for the treatment of inflammatory bowel disease.
Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterised by abdominal pain and bloating in association with altered bowel movements. Its pathogenesis and the underlying molecular mechanisms of visceral hyperalgesia remain elusive. Recent studies of somatic and other visceral pain models suggest a role for purinergic signalling mediated by the P2X receptor (P2XR) family.
To examine the role of P2XR signalling in the pathogenesis in a rat model of IBS-like visceral hyperalgesia.
Visceral hypersensitivity was induced by colonic injection of 0.5% acetic acid (AA) in 10-day-old rats and experiments were conducted at 8 weeks of age. Dorsal root ganglion (DRG) neurons innervating the colon were labelled by injection of DiI (1,1'-dioleyl-3,3,3',3-tetramethylindocarbocyanine methanesulfonate) fluorescence into the colon wall.
Visceral hypersensitivity was reversed by TNP-ATP (2'-(or-3')-O-(trinitrophenyl) ATP), a potent P2X1, P2X3 and P2X2/3 receptor antagonist. Rapid application of ATP (20 µM) induced a fast inactivating current in colon-specific DRG neurons from both control and AA-treated rats. There was a twofold increase in the peak ATP responses in neurons from AA-treated rats. These currents were sensitive to TNP-ATP (100 nM). Under current-clamped conditions, ATP evoked a larger membrane depolarisation in neurons from neonatal AA-treated rats than in controls. P2X3R protein expression was significantly enhanced in colon-specific DRGs 8 weeks after neonatal AA treatment.
These data suggest that the large enhancement of P2XR expression and function may contribute to the maintenance of visceral hypersensitivity, thus identifying a specific neurobiological target for the treatment of chronic visceral hyperalgesia.
Bowel cancer screening using faecal occult blood testing and colonoscopy is currently being rolled out across England. Guidelines recommend that people identified by colonoscopy as having intermediate- or high-risk bowel polyps be offered periodic surveillance colonoscopy because of their elevated risk of bowel cancer. We make projections of the likely year-on-year increase in volumes and spending on colonoscopy due to the screening and surveillance programmes.
We constructed a model based on current bowel cancer screening and surveillance guidelines using screening outcome measures taken from the second round of the English bowel screening pilot. This was then used to predict colonoscopy volumes and cost for a hypothetical population.
For a hypothetical population of 500 000 people, with average deprivation and 66 956 subjects aged 60–74 years, the initial screening and surveillance round would be expected to detect 34 cancers at a cost of £394 157. In the first 8 years, colonoscopy numbers will grow at a rate of 23 per year, most of which will be surveillance colonoscopies. Colonoscopy costs may grow by £11 808 yearly in the same period, representing a cost per eligible person of £2.86 initially, increasing by £0.13 every year. Sensitivity analyses suggest significant changes in these predictions if screening uptake changes by 20%.
The model has been used to make projections for five primary care trusts within the South Central Strategic Health Authority. Results from the volume and cost projections can inform service planning and resource allocation at local levels for the implementation of the current and future bowel cancer screening programme.
To detect precancerous dysplasia or asymptomatic cancer, patients suffering from inflammatory bowel disease often undergo colonoscopic surveillance based on American or British guidelines. It is recommended that surveillance is initiated after 8–10 years of extensive colitis, or after 15–20 years for left-sided disease. These starting points, however, are not based on solid scientific evidence. Our aim was to assess the time interval between onset of inflammatory bowel disease (IBD) and colorectal carcinoma (CRC), and subsequently evaluate how many patients developed cancer before their surveillance was recommended to commence.
A nationwide automated pathology database (PALGA) was consulted to identify patients with IBD-associated colorectal carcinoma in seven university medical centres in The Netherlands between January 1990 and June 2006. Data were collected retrospectively from patient charts. Time intervals between onset of disease and cancer diagnosis were calculated in months.
149 patients were identified with confirmed diagnoses of IBD and CRC (ulcerative colitis n = 89/Crohn’s disease n = 59/indeterminate colitis n = 1). Taking date of diagnosis as the entry point, 22% of patients developed cancer before the 8 or 15 year starting points of surveillance, and 28% if surveillance was commenced 10 or 20 years after diagnosis for extensive or left-sided disease, respectively. Using onset of symptoms to calculate the time interval, 17–22% of patients would present with cancer prior to the surveillance starting points.
These results show that the diagnosis of colorectal cancer is delayed or missed in a substantial number of patients (17–28%) when conducting surveillance strictly according to formal guidelines.
MUTYH-associated polyposis (MAP) is a recessive trait characterised by multiple colorectal adenomas and a high risk of colorectal cancer. MUTYH functions in the DNA base excision repair pathway and has a key role in the repair of oxidative DNA damage.
To assess the contribution of inherited variants in genes involved in base excision repair and oxidative DNA damage including MUTYH, OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1 to the multiple colorectal adenoma phenotype.
Inherited variants of MUTYH, OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1 were sought in 167 unrelated patients with multiple colorectal adenomas whose family histories were consistent with recessive inheritance. These variants were also characterised in ~300 population controls.
Thirty-three patients (20%) and no controls were MUTYH homozygotes or compound heterozygotes (ie, carried two mutations) and therefore had MAP. Eight different pathogenic MUTYH mutations were identified, of which four were novel. MAP cases had significantly more adenomas than non-MAP cases (p = 0.0009; exact test for trends in proportions) and presented earlier (p = 0.013; analysis of variance). Twenty-four protein-altering variants were identified upon screening of OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1. However, all combinations of two (or more) variants that were identified at an individual locus in patients were also seen in controls, and no variants were significantly over-represented (or under-represented) in cases.
Multiple rare alleles of MUTYH are associated with autosomal recessive MAP, while OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1 do not contribute significantly to autosomal recessive polyposis.
Simple card collection systems are becoming available for faecal immunochemical tests (FITs) as well as guaiac faecal occult blood tests (gFOBTs). FITs are now obtainable that allow quantitation of haemoglobin, so that the analytical detection limit can be set to give a positivity rate that is manageable in terms of the available colonoscopy. A combination of a card collection device and an automated FIT analytical system could be advantageous.
The quantitation of haemoglobin in samples collected on cards with a new analytical system and the relationship between faecal haemoglobin concentration and pathology were investigated in a cohort of gFOBT-positive individuals.
All groups had large ranges of haemoglobin concentration and there was overlap between the groups. Median haemoglobin concentrations in participants with normal findings on colonoscopy (167), diverticular disease (43), hyperplastic polyps (41), low risk adenoma (63), higher risk adenoma (35) and cancer (27) were 13.5, 15.6, 16.8, 15.2, 65.6 and 168.9 ng/ml haemoglobin, respectively. Those with diverticular disease, hyperplastic polyps and low risk adenoma were not significantly different from the normal group (p>0.2), but those with higher risk adenoma had significantly higher concentrations (p<0.001), as did those with cancer (p<0.001). Receiver operating characteristic analysis demonstrates that the cut-off concentration can be set to give appropriate clinical characteristics; optimum sensitivity and specificity are achieved at 26.7 ng/ml.
The haemoglobin in faeces on simple FIT card collection devices can be immunoturbidimetrically analysed quantitatively, and the concentration relates to the presence or absence of significant neoplastic disease.
Several pharmacological agents for the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) have been studied. Clinical trials evaluating the protective effect of non-steroidal anti-inflammatory drugs (NSAIDs) have yielded inconclusive results.
To perform a meta-analysis of studies evaluating the effect of prophylactic rectal NSAIDs on PEP.
By searching Medline, Embase, meeting abstracts and bibliographies, two independent reviewers systematically identified prospective randomised controlled trials (RCTs) examining the effect of rectally administered prophylactic NSAIDs on the incidence of PEP pancreatitis. A meta-analysis of these clinical trials was performed.
Four RCTs, enrolling a total of 912 patients, have been published. Meta-analysis of these studies demonstrates a pooled relative risk for PEP after prophylactic administration of NSAIDs of 0.36 (95% CI 0.22 to 0.60); patients who received NSAIDs in the periprocedural period were 64% less likely to develop pancreatitis and 90% less likely to develop moderate to severe pancreatitis. The pooled number needed to treat with NSAIDs to prevent one episode of pancreatitis is 15 patients. No adverse events attributable to the use of NSAIDs were reported in any of the clinical trials.
In this meta-analysis, prophylactic NSAIDs were effective in preventing PEP. Widespread prophylactic administration of these agents may significantly reduce the incidence of PEP, resulting in major clinical and economic benefit. Given current scepticism regarding the efficacy of any prophylactic medication for ERCP, additional multicentre studies are needed for confirmation prior to widespread adoption of this strategy.
Unsafe injections and transfusions used during treatments are considered to be responsible for many cases of transmission of hepatitis C virus (HCV) in developing countries, but cannot account for a substantial proportion of present infections. The aim of the present work was to investigate familial clustering of HCV infection in a population living in a highly endemic area.
A large seroepidemiological survey was conducted on 3994 subjects (age range, 2–88 years) from 475 familial clusters in an Egyptian rural area. Epidemiological methods appropriate for the analysis of correlated data were used to estimate risk factors and familial dependences for HCV infection. A phylogenetic analysis was conducted to investigate HCV strain similarities within and among families.
HCV familial correlations adjusted for known risk factors, similarities between viral strains.
Overall HCV seroprevalence was 12.3%, increasing with age. After adjustment for relevant risk factors, highly significant intrafamilial resemblances in HCV seroprevalence were obtained between father–offspring (odds ratio (OR) = 3.4 (95% confidence interval (CI), 1.8 to 6.2)), mother–offspring (OR = 3.8 (95% CI, 2.5 to 5.8)), and sibling–sibling (OR = 9.3 (95% CI, 4.9 to 17.6)), while a weaker dependence between spouses (OR = 2.2 (95% CI, 1.3 to 3.7)) was observed. Phylogenetic analysis showed greater HCV strain similarity between family members than between unrelated subjects, indicating that correlations can be explained, in part, by familial sources of virus transmission. In addition, refined dissection of correlations between first-degree relatives supported the role of host genes predisposing to HCV infection.
Current HCV infection in endemic countries has a strong familial component explained, at least partly, by specific modes of intrafamilial viral transmission and by genetic predisposition to infection.
Chronic biliary obstruction provokes fibrosis and accumulation of immature ductular cells. This fibroductular reaction resolves following biliary decompression, suggesting that it may also be involved in the repair of biliary damage. The hedgehog (Hh) pathway becomes activated in liver after bile duct ligation (BDL), and might modulate hepatic remodelling because Hh ligands are potent morphogens.
To study the induction of the Hh pathway during progression and resolution of biliary fibrosis, and to clarify whether Hh signalling regulates accumulation of bile duct progenitor cells.
Livers from rats with BDL were examined by quantitative real-time polymerase chain reaction analysis and immunohistochemistry to identify factors that might stimulate Hh signalling. BDL rats were subjected to Roux-en-Y hepaticojejunostomy (R-Y) to relieve biliary obstruction in order to determine whether these factors and Hh signalling declined as ductular populations and concomitant fibrosis regressed. Cultures of immature ductular cells were treated with putative Hh inducers and Hh ligands to confirm their functional relevance.
BDL increased expression of platelet-derived growth factor-BB (PDGF-BB) and sonic hedgehog (Shh), downregulated hedgehog-interacting protein (Hip), activated Hh signalling, and expanded populations of Hh-responsive ductular cells that expressed pancyotkeratin, a liver progenitor cell marker. After R-Y, Hip remained suppressed, expression of PDGF-BB and Shh gradually declined, and populations of hedgehog-responsive ductular cells regressed. In cultured ductular cells, PDGF-BB treatment induced Shh expression, and incubation with Shh inhibited apoptotic activity.
These results identify a mechanism for activation of the Hh pathway during cholestasis and suggest that Hh signalling regulates ductular cell accumulation after biliary injury.
Waist circumference is widely accepted as a risk factor for cardiovascular disease and metabolic syndrome. Non-alcoholic fatty liver disease (NAFLD) is a feature of the metabolic syndrome. A contribution of metabolic syndrome, and especially of waist circumference, to liver fibrosis in children with NAFLD is strongly suspected.
Cross-sectional study.
Department of Hepatogastroenterology and Nutrition, Paediatric Hospital "Bambino Gesù", Rome, Italy.
197 consecutive Caucasian children with NAFLD (136 males and 61 females) aged 3–19 years.
Multivariable logistic regression models were used to examine the contribution of gender, age, body mass index (BMI) and metabolic syndrome components (waist circumference, high-density lipoprotein (HDL)-cholesterol, triglycerides, blood pressure and glucose) to the odds of liver fibrosis as detected by liver biopsy.
92% of the children had BMI >=85th percentile and 84% had a waist >=90th percentile for gender and age. Ten per cent of the children had metabolic syndrome and 67% had liver fibrosis, mostly of low degree. At multivariable analysis, waist was the only metabolic syndrome component to be associated with liver fibrosis. This was seen both when the components of the metabolic syndrome were coded as dichotomous (odds ratio (OR) = 2.40; 95% confidence interval (CI), 1.04 to 5.54) and continuous (OR = 2.07; 95% CI, 1.43 to 2.98 for a 5 cm increase). In the latter case, age was also associated with the outcome (OR = 0.70; 95% CI, 0.55 to 0.89 for a 1 year increase).
Abdominal rather than generalised obesity contributes to liver fibrosis in children with NAFLD. Waist is also the only component of the metabolic syndrome to be associated with fibrosis in these children. Therefore, the presence of abdominal obesity is an additional criterion for the selection of children and adolescents who should undergo extensive investigation, including liver biopsy.
Transient elastography (TE) has received increasing attention as a means to evaluate disease progression in patients with chronic liver disease.
To assess the value of TE for predicting the stage of fibrosis.
Liver biopsy and TE were performed in 150 consecutive patients with chronic hepatitis C-related hepatitis (92 men and 58 women, age 50.6 (SD 12.5) years on the same day. Necro-inflammatory activity and the degree of steatosis at biopsy were also evaluated.
The areas under the curve for the prediction of significant fibrosis (>=F2), advanced fibrosis (>=F3) or cirrhosis were 0.91, 0.99 and 0.98, respectively. Calculation of multilevel likelihood ratios showed that values of TE <6 or >=12, <9 or >=12, and <12 or >=18, clearly indicated the absence or presence of significant fibrosis, advanced fibrosis, and cirrhosis, respectively. Intermediate values could not be reliably associated with the absence or presence of the target condition. The presence of inflammation significantly affected TE measurements in patients who did not have cirrhosis (p<0.0001), even after adjusting for the stage of fibrosis. Importantly, TE measurements were not influenced by the degree of steatosis.
TE is more suitable for the identification of patients with advanced fibrosis than of those with cirrhosis or significant fibrosis. In patients in whom likelihood ratios are not optimal and do not provide a reliable indication of the disease stage, liver biopsy should be considered when clinically indicated. Necro-inflammatory activity, but not steatosis, strongly and independently influences TE measurement in patients who do not have cirrhosis.